Significant increases in multidrug-resistant Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae) have been noted over the past decade. The most common of these are the extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-EB). ESBL-EB infections are strongly associated with increased morbidity, mortality, and cost. Furthermore, there are few, and sometimes no, therapeutic options available to treat these infections. While historically limited to healthcare settings, ESBL-EB has increasingly been found in the community. The emergence of ESBL-EB in non-healthcare settings is of great concern as Enterobacteriaceae cause the vast majority of urinary tract infections (UTIs) in the community. Furthermore, UTIs are the most common outpatient bacterial infection with significant clinical and economic implications. Effective strategies to address the emergence of community-onset ESBL-EB UTIs are unknown due to the incomplete understanding of the epidemiology of these infections. Furthermore, the impact of community-onset ESBL-EB infections on antibiotic treatment decisions and clinical outcomes remains poorly understood. The carbapenem antibiotics remain the therapy of choice for ESBL-EB infections. However, in the past few years, K. pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) have increased significantly. While still much less common that ESBL-EB, these carbapenem-resistant organisms further complicate treatment of ESBL-EB. However, the epidemiology and impact of KPC-KP UTIs have not been studied. The primary aims of this application are: 1) To identify the phenotypic and genotypic characteristics of ESBL-EB causing community-onset UTIs; 2) To elucidate risk factors for community-onset ESBL-EB UTI; 3) To develop and validate a clinical prediction rule for community-onset ESBL-EB UTI; and 4) To identify the clinical impact of community-onset ESBL-EB UTI The primary hypotheses for these aims are that ESBL-EB UTI is associated with prior antibiotic use and that ESBL-EB UTIs are associated with clinical failure. The secondary aims of this application are: 1) To identify the phenotypic and genotypic characteristics of KPC-KP causing community-onset UTIs; 2) To elucidate risk factors for community-onset KPC-KP UTI; 3) To develop and validate a clinical prediction rule for community-onset KPC-KP UTI; and 4) To identify the clinical impact of community-onset KPC-KP UTI. This study will provide crucial information to guide development of strategies to limit further emergence of these organisms. The study will also offer important insights into optimal selection of empiric antimicrobial therapy. Finally, the inclusion of subjects from a diverse network of ambulatory care sites within an established research network will significantly strengthen the generalizability of the results of this study. PUBLIC HEALTH RELEVANCE: Community-onset urinary tract infections (UTIs) due to extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-EB) have increased significantly in recent years. This study will investigate risk factors for ESBL-EB UTIs, develop and validate a clinical prediction rule for these infections, and identify the clinical impact of ESBL-EB UTIs. Results from this study will be vital for designing future interventions to limit further increases in ESBL-EB infections in ambulatory settings and optimize empiric antibiotic use for outpatient UTIs.